The present invention relates to 6-substituted heteroquinolinecarboxylic acid derivatives and their addition salts effective for the therapy of disorder of cerebral nerve cells as antagonists against excitatory amino acid receptors, in particular, as selective antagonists against AMPA receptor in non-NMDA receptor, processes for the preparation of both, and a medicinal composition containing these compounds.
The glutamic acid being excitatory amino acid is a main excitatory transmitter substance in the central nervous system of vertebrates, and is known as an amino acid contained most rich in brain. It is known, however, that, when releasing from nervous axon terminals exceeding the physiological threshold, it excessively excites the glutamic acid receptor of post-synapse to cause the death of nerve cells. This is called excitotoxicity.
In recent years, it has been clarified that the death of nerve cells due to glutamic acid concerns deeply in various diseases of cerebral nerve such as cerebral hemorrhage, head trauma, epilepsy, Huntington""s disease, Parkinson""s disease, amyotrophic lateral sclerosis and Alzheimer""s disease. It is considered therefore that, if such excitotoxicity could be prevented effectively, a potential to the therapy for these intractable diseases, for which there are virtually no therapeutic means at present, would be opened.
Roughly classifying, the glutamic acid receptor is divided into ion channel type receptor and G protein-binding type receptor, and this ion channel type receptor is further divided into NMDA (N-methyl-D-aspartic acid) receptor and non-NMDA receptor. Moreover, the latter non-NMDA receptor is classified into AMPA (xcex1-amino-3-hydroxy-5-methyl-4-isooxazol-propionic acid) receptor and KA (kainic acid) receptor.
Studies on these excitatory amino acid receptors are being put forward, and, above all, with the drug with antagonism against AMPA receptor in non-NMDA receptor, it is known that the adverse effects (learning and memory disturbances, schizophrenia-like symptom, etc.), which the drugs (MK-801 etc.) with antagonism against NMDA receptor have, are not expressed (Neurosci. Biobehav. Rev., 1992, 16, 13-24; J. Pharmacol. Exp. Ther., 1958, 245, 969-974), and that the protective effect on cerebral nerve can be expected even by the administration after ischemia (Science, 1990, 247, 571-574).
Moreover, with the compounds with quinoxalinedione structure and with antagonism against AMPA receptor such as NBQX, drawbacks of causing kidney disturbance that is considered based on physicochemical properties, and the like are reported (J. Cereb. Blood Flow Metab., 1994, 14, 251-261), hence they cannot be said to be satisfactory compounds.
Now, as the compounds with similar structure to quinolinecarboxylic acid derivatives, compounds represented by a general formula (13) 
(wherein R1 denotes aldehyde group, amide group, carboxyl group, etc. and R2 denotes hydrogen atom), described in Korean J. Med. Chem., 5 (1), 28-37 (1995) by Dong-A Pharmaceutical Research Laboratories as compounds with antagonism against angiotensin II, compounds represented by a general formula (14) 
(wherein R denotes hydrogen atom or alkyl group, R1 and R2 denote hydrogen atoms, halogens, alkyl groups, alkoxycarbonyl groups, nitro groups, cyano groups, etc., R3 denotes hydrogen atom, alkyl group, aryl group or aralkyl group, or R3 is absent, A denotes CO, CS, etc., Z denotes nitrogen atom when R3 is absent and Dxe2x80x94Z is single bond, or Z is carbon atom, D denotes Cxe2x80x94R when Dxe2x80x94Z is double bond, X denotes oxygen atom, Nxe2x80x94R, etc., and Y denotes substituted aminoalkyl group, quinuclidyl group, etc.), described in EP 382687 by Instituto De Angeli S.p.A, as compounds with antimuscarine function, and compounds represented by a general formula (15) 
(wherein R1 denotes cyano group, carboxyl group, alkoxycarbonyl group, amide group, nitro group, acetylamino group, etc., X denotes oxygen atom etc., Y denotes oxygen atom, sulfur atom or NH, R2 and R4 denote hydrogen atoms, hydroxyl groups, amino groups, trifluoromethyl groups, alkyl groups, etc., R3 denotes hydroxyl group, amino group, alkylamino group, nitroso group, trifluoromethyl group, etc., and R5 denotes hydroxyl group, alkyl group, halogen atom, etc.), described in WO93/16064 by Biosignal Co. as compounds with anticancer function (tyrosinekinase inhibitory function), are known. However, none of these compounds as described above have asymmetric substituents at 6- and 7-positions, and it is also not described that they have the antagonism against AMPA receptor in excitatory amino acid receptors.
Moreover, compounds represented by a general formula (16) 
(wherein X denotes oxygen atom or NH, m denotes 0 to 6, and A denotes haloalkyl group, hydroxyl group, alkoxy group, carboxyl group, cyano group, amide group, etc.), described in WO95/31455 by Taisho Pharmaceutical Co. as compounds with antagonism against serotonin 4 receptor, and compounds represented by a general formula (17) 
(wherein X denotes O or NH, and Y denotes 2-(diethylamino)ethyl, 8-methyl-8-azabicyclo-[3,2,1]octa-3-yl, quinuclidine-3-yl, 1-ethylpiperidine-4-yl, etc.), described in Jpn. Kokai Tokkyo Koho JP 08,311,033 by the same company as compounds with antagonism against serotonin 4 receptor, are known. In these compounds, however, no substituents exist on benzene ring, the structure is different from that of the inventive compounds, and it is not described that they have the antagonism against AMPA receptor in excitatory amino acid receptors.
Moreover, compounds represented by a general formula (18) 
(wherein R1, R2 and R3 denote hydrogen atoms, halogen atoms, alkyl groups, nitro groups, cyano groups, aminosulfonyl groups, etc., and R4 and R5 denote hydrogen atoms, alkyl groups, etc.), are opened to public in EP 640612 by Adeal et compagnie as compounds with inhibitory action on the pathologic symptoms relevant to hyperactivity through the route of excitatory amino acid, and, as synthetic intermediates of this general formula (18), compounds represented by a general formula (19) 
(wherein R1, R2 and R3 are as described above), and compounds represented by a general formula (20) 
(wherein R1, R2 and R3 are as described above), are transcribed. However, the fact that these synthetic intermediates have the antagonism against AMPA receptor in excitatory amino acid receptors is not described, and, in these compounds, those with substituents at 6- and 7-positions as the inventive compounds are of symmetric type, hence the structure is different from that of the inventive compounds.
Moreover, compounds represented by a general formula (21) 
(wherein R1 and R8 denote hydrogen atoms or alkyl groups, R3 denotes hydrogen atom, alkyl group, carboxyl group, cyano group, etc., R4 denotes hydrogen atom, alkyl group, alkoxy group, etc., R5 denotes hydrogen atom, amino group, etc., R6 denotes hydrogen atom, and R7 denotes hydroxyl group, amino group, alkylamino group, etc.), described in Jpn. Kokai Tokkyo Koho JP 03,162,483 by Pioneer Electronics Co. as compounds for fluorescent material in organic luminescence device, are known. These compounds however are irrelevant to medicinal drugs, and it is not described that they have the antagonism against AMPA receptor in excitatory amino acid receptors as well.
Moreover, recently, compounds represented by a general formula (22) 
(wherein R, R1 and R2 denote hydrogen atoms, chlorine atoms, fluorine atoms or nitro groups, and X denotes carboxylic acid, phosphoric acid, boric acid, amide, etc.), are reported in J. Med. Chem., 39, 197-206 (1996) by Alex A. Cordi et al, with respect to the conversion of functional group at 3-position of 2-oxoquinoline skeleton as antagonists against excitatory amino acid. Among these compounds, however, they aimed to compounds, X being phosphoric acid in the general formula (22), and, in addition, those with asymmetric substituents at 6- and 7-position of quinoline ring as the inventive compounds are not reported. Also, the antagonism against AMPA and the antagonism against glycine reported are not considered to be sufficient.
Moreover, quinolone derivatives are described in WO 93/10783 by Merck Sharp and Dohme Co. as compounds with antagonism against NMDA and AMPA receptors. However, the disclosure of compounds cannot be said to be sufficient, and, in addition, the structure is different from that of the inventive compounds with characteristic substituents at 6-position of quinoline ring.
Moreover, the disclosed pharmacological data are also only for NMDA receptor and no concrete data are disclosed against AMPA receptor, as the inventive compounds.
The invention is to provide compounds with antagonism against receptor of glutamic acid that is considered to be an etiology bringing about the memory disorder or dementia due to said diseases and selective death of cells, in particular, with high affinity and selectivity against AMPA receptor in non-NMDA receptor and protective effect on cerebral nerve cells.
As a result of diligent studies exploring an antagonist against excitatory amino acid receptors effective for the therapy of disorder of cerebral nerve cells, in particular, a selective antagonist against AMPA receptor in non-NMDA receptor, aiming at the development of novel therapeutic agent for the disorder of cerebral nerve cells, the inventors have found that the inventive 6-substituted heteroquinolinecarboxylic acid derivatives and addition salts thereof have excellent antagonism against AMPA receptor.
Namely, according to the invention, it has been found that 6-substituted heteroquinolinecarboxylic acid derivatives represented by a general formula (1) 
(wherein A denotes a single bond or methylene (CH2),
Y denotes a nitrogen atom or xe2x95x90CHxe2x80x94,
V denotes a single bond or methylene (CH2),
T denotes a hydroxyl group, amino group, lower alkoxycarbonyl group, carboxyl group, aldehyde group, general formula (2) 
(wherein X denotes an oxygen atom or sulfur atom, and W denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen, or cycloalkyl group), or general formula (3) 
(wherein X denotes an oxygen atom or sulfur atom, and W denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen, or cycloalkyl group),
R denotes a nitro group, trifluoromethyl group or halogen atom, and
R1 denotes a hydroxyl group or lower alkoxy group), and addition salts thereof have excellent antagonism against AMPA receptor, leading to the completion of the invention.
In the general formula (1) of the inventive compounds, preferably, compounds, R being nitro group, trifluoromethyl group or chloro group, R1 being hydroxyl group or lower alkoxy group, and A being single bond, are mentioned. More preferably, compounds, R being nitro group, trifluoromethyl group or chloro group, R1 being hydroxyl group, V being methylene (CH2), and X being oxygen atom in the general formula (2) or general formula (3) for T, are mentioned. As these preferable compounds, compounds shown below, namely, 1,2-dihydro-7-nitro-2-oxo-6-(4-((phenylcarbamoyloxy)methyl)imidazole-1-yl)quinoline-3-carboxylic acid, 6-(4-(((2-bromophenyl)carbamoyloxy)methyl)imidazole-1-yl)-1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylic acid, 6-(4-(((3-bromophenyl)carbamoyloxy)methyl)imidazole-1-yl)-1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylic acid, 6-(4-(((4-bromophenyl)carbamoyloxy)methyl)imidazole-1-yl)-1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylic acid, 6-(4-(((2-fluorophenyl)carbamoyloxy)methyl)imidazole-1-yl)-1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylic acid, 6-(4-(((4-fluorophenyl)carbamoyloxy)methyl)imidazole-1-yl)-1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylic acid, 1,2-dihydro-6-(4-(((2,4-difluorophenyl)carbamoyloxy)methyl)imidazole-1-yl)-7-nitro-2-oxoquinoline-3-carboxylic acid, 1,2-dihydro-6-(4-(((2,5-difluorophenyl)carbamoyloxy)methyl)imidazole-1-yl)-7-nitro-2-oxoquinoline-3-carboxylic acid, 1,2-dihydro-6-(4-(((4-methoxyphenyl)carbamoyloxy)methyl)imidazole-1-yl)-7-nitro-2-oxoquinoline-3-carboxylic acid, 1,2-dihydro-6-(4-(((4-methylphenyl)carbamoyloxy)methyl)imidazole-1-yl)-7-nitro-2-oxoquinoline-3-carboxylic acid, 1,2-dihydro-7-nitro-2-oxo-6-(4-(((4-trifluoromethylphenyl)carbamoyloxy)methyl)imidazole-1-yl)quinoline-3-carboxylic acid, 6-(4-(((4-ethoxycarbonylphenyl)carbamoyloxy)methyl)imidazole-1-yl)-1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylic acid, 6-(4-(((3-ethoxycarbonylphenyl)carbamoyloxy)methyl)imidazole-1-yl)-1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylic acid, 1,2-dihydro-7-nitro-2-oxo-6-(4-((N-phenylmethylcarbamoyloxy)methyl)imidazole-1-yl)quinoline-3-carboxylic acid, 6-(4-(((3-carboxyphenyl)carbamoyloxy)methyl)imidazole-1-yl)-1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylic acid, 6-(4-(((4-carboxyphenyl)carbamoyloxy)methyl)imidazole-1-yl)-1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylic acid, 6-(4-(((4-carboxy-2-fluorophenyl)carbamoyloxy)methyl)imidazole-1-yl)-1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylic acid, 6-((((2-fluorophenyl)aminocarbonylamino)methyl)imidazole-1-yl)-1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylic acid, 6-((((4-carboxy-2-fluorophenyl)aminocarbonylamino)methyl)imidazole-1-yl)-1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylic acid, 6-((((3-carboxyphenyl)aminocarbonylamino)methyl)imidazole-1-yl)-1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylic acid, 6-((((4-carboxyphenyl)aminocarbonylamino)methyl)imidazole-1-yl)-1,2-dihydro-7-nitro-2-oxoquinoline-3-carboxylic acid, 6-(4-(((4-carboxyphenyl)carbamoyloxy)methyl)imidazole-1-yl)-1,2-dihydro-2-oxo-7-trifluoromethylquinoline-3-carboxylic acid, 6-(4-(((4-carboxymethylphenyl)carbamoyloxy)methyl)imidazole-1-yl)-1,2-dihydro-7-trifluoromethyl-2-oxoquinoline-3-carboxylic acid, 6-(4-(((4-carboxy-2-fluorophenyl)carbamoyloxy)methyl)imidazole-1-yl)-1,2-dihydro-7-trifluoromethyl-2-oxoquinoline-3-carboxylic acid, 6-((((4-carboxyphenyl)aminocarbonylamino)methyl)imidazole-1-yl)-1,2-dihydro-7-trifluoromethyl-2-oxoquinoline-3-carboxylic acid, 6-((((4-carboxymethylphenyl)aminocarbonylamino)methyl)imidazole-1-yl)-1,2-dihydro-7-trifluoromethyl-2-oxoquinoline-3-carboxylic acid, 6-((((4-carboxyphenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-1,2-dihydro-7-trifluoromethyl-2-oxoquinoline-3-carboxylic acid, 6-((((4-carboxymethylphenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-1,2-dihydro-7-trifluoromethyl-2-oxoquinoline-3-carboxylic acid, 6-(4-(((4-carboxyphenyl)carbamoyloxy)methyl)imidazole-1-yl)-7-chloro-1,2-dihydro-2-oxoquinoline-3-carboxylic acid, 6-(4-(((4-carboxymethyl-phenyl)carbamoyloxy)methyl)imidazole-1-yl)-7-chloro-1,2-dihydro-2-oxoquinoline-3-carboxylic acid, 6-((((4-carboxyphenyl)aminocarbonylamino)methyl)imidazole-1-yl)-7-chloro-1,2-dihydro-2-oxoquinoline-3-carboxylic acid, 6-((((4-carboxymethylphenyl)aminocarbonylamino)methyl)imidazole-1-yl)-7-chloro-1,2-dihydro-2-oxoquinoline-3-carboxylic acid, 6-((((4-carboxyphenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-7-chloro-1,2-dihydro-2-oxoquinoline-3-carboxylic acid, 6-((((4-carboxymethylphenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-7-chloro-1,2-dihydro-2-oxoquinoline-3-carboxylic acid, and the like can be mentioned.
Best Embodiment to Put the Invention into Practice
In the description of the general formula (1) of the invention, for xe2x80x9csubstituentsxe2x80x9d in the phrase of xe2x80x9caralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle)xe2x80x9d, halogen atom, hydroxyl group, lower alkyl group which may be substituted with halogen atom, lower alkoxy group, lower alkylthio group, lower alkoxycarbonyl group, nitro group, amino group which may be substituted, cyano group, carboxyl group, aldehyde group, carboxy lower alkyl group, etc. are mentioned, for xe2x80x9clower alkyl groupsxe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 6 such as methyl, ethyl, n-propyl and iso-propyl are mentioned, for xe2x80x9ccycloalkyl groupsxe2x80x9d, ones with carbon atoms of 3 to 7 such as cyclopropyl, cyclopentyl and cyclohexyl are mentioned, for xe2x80x9chalogen atomsxe2x80x9d, fluorine, chlorine, bromine and iodine are mentioned, for xe2x80x9clower alkoxy groupsxe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 4 such as methoxy, ethoxy and propoxy are mentioned, for xe2x80x9clower alkylthio groupsxe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 6 such as methylthio, ethylthio and propylthio are mentioned, for xe2x80x9clower alkoxycarbonyl groupsxe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 4 such as methoxycarbonyl and ethoxycarbonyl are mentioned, for xe2x80x9caralkyloxy groupsxe2x80x9d, benzyloxy, phenylethyloxy and phenylpropyloxy are mentioned, for xe2x80x9caralkylthio groupsxe2x80x9d, benzylthio, phenylethylthio and phenylpropylthio are mentioned, and, for xe2x80x9camino groups which may be substitutedxe2x80x9d, amino groups may be substituted with acyl group or arylsulfonyl group, for example, acetyl, methanesulfonyl, phenylsulfonyl, etc., or they may be substituted with lower alkyl group which may be substituted with 1 to 2 halogen atoms, phenyl group which may have 1 to 2 substituents or aralkyl group which may have 1 to 2 substituents. The substituents referred to so here are xe2x80x9csubstituentsxe2x80x9d as explained above.
Furthermore, in the description, xe2x80x9cheterocyclesxe2x80x9d in the phrase of xe2x80x9caralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle)xe2x80x9d are saturated or unsaturated monocyclic or polycyclic heterocycle groups which may have one or more substituents and which can contain one or more nitrogen, oxygen or sulfur atoms, and, for example, pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, pyridazyl, pyrazyl, etc. are mentioned. xe2x80x9cIts condensed ringxe2x80x9d represents benzene-condensed rings of said xe2x80x9cheterocyclesxe2x80x9d and, for example, indolyl, tetrahydroquinolyl, benzoxazolidinyl, benzothiazolidinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, cinnolyl, etc. are mentioned.
The compounds of the invention are prepared, for example, through preparative processes shown below.
Compounds represented by the general formula (1) can be synthesized by reacting compounds represented by a general formula (4) 
(wherein A, Y, V, T, R and R1 are as described above, and R2 denotes a lower alkyl group which may be substituted with halogen atom or aralkyl group which may have one or more substituents), for 0.5 to 72 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent, for example, water, acetic acid, methanol or the like, using a suitable acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, mixed acid thereof or the like.
Moreover, compounds represented by the general formula (1) can also be synthesized, in the case of R1 being lower alkoxy group among compounds represented by the general formula (4) 
(wherein A, Y, V, T, R, R1 and R2are as described above), by reacting those compounds for 0.5 to 72 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, water, methanol, ethanol or the like, using a suitable alkali, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide or the like to convert to carboxylic acid, and then reacting for 0.5 to 72 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent, for example, water, acetic acid, methanol or the like, using a suitable acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, mixed acid thereof or the like.
Moreover, compounds represented by the general formula (1) can also be synthesized, in the case of R1 being lower alkoxy group among compounds represented by the general formula (4) 
(wherein A, Y, V, T, R, R1 and R2 are as described above), by reacting those compounds for 3 to 72 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent, for example, water, acetic acid, methanol or the like, using a suitable acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, mixed acid thereof or the like to deprotect R2, and then reacting for 0.5 to 72 hours at 20 to 100xc2x0 C. in a solvent of water, methanol, ethanol or the like, using a suitable alkali, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide or the like.
Moreover, compounds, R1 being lower alkoxy group among compounds represented by the general formula (1), those compounds are reacted for 0.5 to 10 hours at 20 to 100xc2x0 C. in a suitable solvent of water, methanol, ethanol or the like, using a suitable alkali, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide or the like to synthesize compounds, R1 being hydroxyl group.
Moreover, compounds, Y being xe2x95x90CHxe2x80x94 among compounds represented by the general formula (1) can also be synthesized by reacting compounds represented by a general formula (5) 
(wherein A, R and R1 are as described above), with compounds represented by a general formula (6) 
(wherein T and V are as described above, and R3 denotes a lower alkyl group which may be substituted with halogen or aralkyl group which may have one or more substituents), for 0.5 to 5 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent, for example, tetrahydrofuran, benzene, toluene, acetic acid, ethanol, methanol or the like (suitable inorganic or organic acid, for example, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or the like may be added).
Moreover, compounds, T being represented by the general formula (2) or general formula (3) among compounds represented by the general formula (1), can also be synthesized by reacting compounds represented by a general formula (7) 
(wherein A, Y, V, R and R1 are as described above, and T1 denotes a hydroxyl group or amino group), with compounds represented by a general formula (8)
Zxe2x80x94Nxe2x95x90Cxe2x95x90Xaxe2x80x83xe2x80x83(8)
(wherein Z denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle or its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen, or cycloalkyl group, and Xa denotes an oxygen or sulfur atom), for 1 to 15 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable organic base, for example, triethylamine, pyridine or the like.
Moreover, they can also be synthesized by converting compounds represented by a general formula (9)
Zxe2x80x94A1xe2x80x94Dxe2x80x83xe2x80x83(9)
(wherein Z is as described above, A1 denotes single bond, and D denotes an amino group, carboxyl group, amide group or lower alkoxycarbonyl group), to isocyanic (isothiocyanic) esters or carbamic chlorides through already known process, in place of the general formula (8), and then reacting with general formula (7) similarly to general formula (8).
For example, in the case of D being amino group, they can be converted to carbamic chlorides or isocyanic (isothiocyanic) esters by reacting with phosgene (thiophosgene), phosgene dimer (2,2,2-trichloromethyl chloroformate) or its homologue (4-nitrophenyl chloroformate etc.) for 1 to 5 hours at xe2x88x9210 to 50xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, benzene, toluene or the like, without base or using a suitable organic base, for example, triethylamine or the like. Further, they can be converted to isocyanic (isothiocyanic) esters by using Crutius rearrangement reaction or Schmidt rearrangement reaction after converted carboxyl group to acid azide in the case of D being carboxyl group, and by using Hofmann rearrangement reaction in the case of D being amide group. Moreover, in the case of D being carboxyl group, it is also possible to convert to isocyanic (isothiocyanic) esters in one pot using DPPA (diphenylphosphoryl azide).
Moreover, compounds represented by the general formula (1) can also be synthesized by reacting compounds represented by a general formula (23) 
(wherein A, Y, V, T and R are as described above), with malonic diesters represented by a general formula (24) 
(wherein R4 denotes a lower alkyl group), for 2 to 24 hours at 25 to 100xc2x0 C. in a suitable solvent, for example, ethanol, methanol, tetrahydrofuran or the like, in the presence of a suitable base, for example, sodium ethoxide, sodium methoxide, potassium ter-butoxide, potassium hydroxide or the like.
Moreover, compounds represented by the general formula (1) can be synthesized by reacting compounds represented by a general formula (25) 
(wherein A, R and R1 are as described above, and Xb denotes a halogen atom), with compounds represented by a general formula (12) 
(wherein Y, V and T are as described above), for 0.5 to 24 hours at 20 to 160xc2x0 C. without solvent or in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like.
Moreover, compounds, T being represented by the general formula (2) or general formula (3) among compounds represented by the general formula (4), can also be synthesized by reacting compounds represented by a general formula (10) 
(wherein A, Y, V, R, R1, R2 and T1 are as described above), with compounds represented by the general formula (8)
Zxe2x80x94Nxe2x95x90Cxe2x95x90Xaxe2x80x83xe2x80x83(8)
(wherein Z and Xa are as described above), for 1 to 15 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable organic base, for example, triethylamine, pyridine or the like.
Moreover, they can also be synthesized by converting compounds represented by a general formula (9)
xe2x80x83Zxe2x80x94A1xe2x80x94Dxe2x80x83xe2x80x83(9)
(wherein Z, A1 and D are as described above), to isocyanic (isothiocyanic) esters or carbamic chlorides through already known process, in place of the general formula (8), and then reacting with general formula (7) similarly to general formula (8).
For example, in the case of D being amino group, they can be converted to carbamic chlorides or isocyanic (isothiocyanic) esters by reacting with phosgene (thiophosgene), phosgene dimer (2,2,2-trichloromethyl chloroformate) or its homologue (4-nitrophenyl chloroformate etc.) for 1 to 5 hours at xe2x88x9210 to 50xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, benzene, toluene or the like, without base or using a suitable organic base, for example, triethylamine or the like.
Further, they can be converted to isocyanic (isothiocyanic) esters by using Crutius rearrangement reaction or Schmidt rearrangement reaction after converted carboxyl group to acid azide in the case of D being carboxyl group, and by using Hofmann rearrangement reaction in the case of D being amide group. Moreover, in the case of D being carboxyl group, it is also possible to convert to isocyanic (isothiocyanic) esters in one pot using DPPA (diphenylphosphoryl azide).
Moreover, compounds represented by the general formula (4) can be synthesized by reacting compounds represented by a general formula (11) 
(wherein A, Xb, R, R1 and R2 are as described above), with compounds represented by a general formula (12) 
(wherein Y, T and V are as described above), for 0.5 to 24 hours at 20 to 160xc2x0 C. without solvent or in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like.
Here, compounds, A being single bond among compounds represented by the general formula (11), can be synthesized by reacting compounds represented by a general formula (25) 
(wherein A, Xb, R and R1 are as described above), with alkyl halide, for example, methyl iodide or the like, or aralkyl halide, for example, 4-methoxybenzyl chloride or the like, for 2 to 10 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, benzene, toluene, chloroform, methylene chloride, tetrahydrofuran or the like, using a suitable silver catalyst, for example, silver oxide, silver carbonate or the like.
Moreover, they can also be synthesized by reacting compounds represented by the general formula (25) for 2 to 6 hours at 0 to 120xc2x0 C. in a suitable solvent, for example, benzene, toluene, chloroform, methylene chloride, tetrahydrofuran or the like, using borate, for example, tetramethyloxonium borate or the like.
Moreover, compounds, A being methylene (CH2) among compounds represented by the general formula (11) can be synthesized by reacting compounds represented by a general formula (26) 
(wherein R, R1 and R2 are as described above), for 1 to 12 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, carbon tetrachloride, chloroform, acetic acid or the like, using a halogenating agent, for example, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine or the like.
Moreover, compounds represented by the general formula (5) can be synthesized by reacting compounds represented by a general formula (27) 
(wherein A, R, R1 and R2 are as described above, and R5 and R6 identically or differently denote hydrogen atoms or protective groups of amino group), for 3 to 72 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, water, acetic acid, methanol, ethanol or the like, using a suitable acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, mixed acid thereof or the like.
Here, compounds represented by the general formula (27) can be synthesized by reacting compounds represented by the general formula (11) 
(wherein A, R, R1, R2 and Xb are as described above), with general formula (28)
R5R6xe2x80x94NHxe2x80x83xe2x80x83(28)
(wherein R5 and R6 are as described above), for 0.5 to 48 hours at 20 to 160xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like.
Moreover, compounds (31), A being single bond and R being trifluoromethyl group among compounds represented by the general formula (5), can be synthesized through publicly known processes shown in Scheme 1. 
(wherein R1 is as described above)
Namely, compounds (29) are reacted with malonic esters, for example, diethyl malonate or the like, for 2 to 24 hours at 25 to 100xc2x0 C. in a suitable solvent, for example, alcohol such as ethanol or methanol, tetrahydrofuran, N,N-dimethylformamide or the like, in the presence of a suitable base, for example, sodium ethoxide, potassium ter-butoxide, potassium hydroxide or the like, to convert to compounds (30), and then these are subject to reduction through catalytic hydrogenation, that is, hydrogenated for 2 to 24 hours at 25 to 80xc2x0 C. and at ambient pressure to 5 atm (507 KPa) in a suitable solvent, for example, ethanol, methanol, acetic acid or the like in the presence of a suitable catalyst, for example, palladium on carbon, platinum oxide, rhodium on alumina or the like, thus allowing to synthesize compounds (31). Also, they can be synthesized by reacting compounds (30) for 1 to 7 hours at 25 to 100xc2x0 C. in a suitable solvent, for example, ethanol, dilute hydrochloric acid, acetic acid or mixed solvent thereof in the presence of tin chloride, zinc, iron, sodium hydrosulfite or the like.
Here, compound represented by the general formula (29) can be synthesized as shown in following Scheme 2. 
Namely, available or synthesizable compound (32) is reacted for 0.5 to 2 hours at xe2x88x9210 to 80xc2x0 C. in a suitable solvent, for example, nitromethane, acetic acid, sulfuric acid or the like, using a suitable nitrating agent, for example, concentrated nitric acid, fuming nitric acid, potassium nitrate, acetyl nitrate or the like to convert to compound (33), and this is subject to reduction through catalytic hydrogenation, that is, hydrogenated for 2 to 24 hours at 25 to 80xc2x0 C. and at atmospheric pressure to 5 atm (507 KPa) in a suitable solvent, for example, ethanol, methanol, acetic acid or the like in the presence of a suitable catalyst, for example, palladium on carbon, platinum oxide, rhodium-alumina or the like, followed further by aceylation, to convert to compound (34). This is reacted for 0.5 to 2 hours at xe2x88x9210 to 80xc2x0 C. in a suitable solvent, for example, nitromethane, acetic acid, sulfuric acid or the like, using a suitable nitrating agent, for example, concentrated nitric acid, fuming nitric acid, potassium nitrate, acetyl nitrate or the like to convert to compound (35), then this is reacted for 1 to 15 hours at 0 to 120xc2x0 C. in a suitable solvent, for example, water, acetone or the like, using a suitable oxidizing agent, for example, potassium permanganate, sodium periodate or the like to convert to compound (36), and successively this is hydrolyzed for 1 to 10 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, water, ethanol, methanol or the like or mixed solution thereof, using a suitable base, for example, sodium hydroxide, potassium hydroxide or the like, or it is hydrolyzed for 1 to 10 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, water, ethanol, methanol or the like or mixed solution thereof, using a suitable acid, for example, hydrochloric acid, hydrobromic acid or the like, thereby converting to compound (37). Next, compound (37) is reacted for 1 to 10 hours at 20 to 150xc2x0 C. in a suitable solvent, for example, ether, tetrahydrofuran, dioxane or the like, using a suitable reducing agent, for example, borane complex such as borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, borane-pyridine complex or the like to convert to compound (38), and further this is reacted for 1 to 24 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, chloroform, methylene chloride, tetrahydrofuran or the like, using a suitable oxidizing agent, for example, manganese dioxide or the like, thus allowing to convert to compound (29).
Moreover, compounds, A being single bond among compounds represented by the general formula (23), can be synthesized as shown in following Scheme 3. 
(wherein Y, V, T and R are as described above)
Namely, available or synthesizable general formula (39) is reacted for 1 to 5 hours at xe2x88x9278 to 25xc2x0 C. in a suitable solvent, for example, ether, tetrahydrofuran or the like in the presence of chloroform, using an organic base, for example, potassium ter-butoxide or the like to convert to general formula (40), and these are reacted with compounds represented by general formula (12) 
(wherein Y, T and V are as described above), for 0.5 to 24 hours at 20 to 160xc2x0 C. without solvent or in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like to convert to general formula (41).
These are reacted for 10 to 30 minutes at 20 to 80xc2x0 C. in a suitable solvent, for example, water, acetic acid, mixed solvent thereof or the like, using a suitable reducing agent, for example, titanium trichloride or the like, and then brought to alkaline with a suitable alkali, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide or the like, thus allowing to convert to general formula (23).
Moreover, compounds, A being single bond among compounds represented by the general formula (25), can be synthesized through publicly known process (Scheme 4). 
(wherein R, R1 and Xc are as described above)
Namely, they can be synthesized by reacting general formula (42) with malonic esters, for example, diethyl malonate or the like, for 2 to 24 hours at 25 to 100xc2x0 C. in a suitable solvent, for example, alcohol such as ethanol or methanol, tetrahydrofuran, N,N-dimethylformamide or the like in the presence of a suitable base, for example, sodium ethoxide, potassium ter-butoxide, potassium hydroxide or the like.
Here, compounds, R being nitro group among compounds represented by general formula (42), can be synthesized through processes shown in following Scheme 5. 
(wherein Xc is as described above)
Namely, available or synthesizable general formula (43) are acetylated with acetic anhydride at room temperature to convert to general formula (44), these are reacted for 0.5 to 2 hours at xe2x88x9210 to 80xc2x0 C. in a suitable solvent, for example, nitromethane, acetic acid, sulfuric acid or the like, using a suitable nitrating agent, for example, concentrated nitric acid, fuming nitric acid, potassium nitrate, acetyl nitrate or the like to convert to general formula (45), and these are reacted for 1 to 15 hours at 0 to 120xc2x0 C. in a suitable solvent, for example, water, acetone or the like, using a suitable oxidizing agent, for example, potassium permanganate, sodium periodate or the like to convert to general formula (46). These are hydrolyzed for 1 to 10 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, water, ethanol, methanol, mixed solution thereof or the like, using a suitable base, for example, sodium hydroxide, potassium hydroxide or the like, or they are hydrolyzed for 1 to 10 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, water, ethanol, methanol or the like or mixed solution thereof, using a suitable acid, for example, hydrochloric acid, hydrobromic acid or the like, thereby converting to general formula (47). Next, general formula (47) are reacted for 1 to 10 hours at 20 to 150xc2x0 C. in a suitable solvent, for example, ether, tetrahydrofuran, dioxane or the like, using a suitable reducing agent, for example, borane complex such as borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, borane-pyridine complex or the like to convert to general formula (48), and successively these are reacted for 1 to 24 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, chloroform, methylene chloride, tetrahydrofuran or the like, using a suitable oxidizing agent, for example, manganese dioxide or the like, thus allowing to convert to general formula (42).
Moreover, compounds, R being nitro group among compounds represented by the general formula (26), can be synthesized through processes shown in following Scheme 5. 
(wherein R1 and R2 are as described above)
Namely, available general formula (49) is acetylated with acetic anhydride at room temperature to convert to general formula (50), this is reacted for 0.5 to 2 hours at xe2x88x9210 to 80xc2x0 C. in a suitable solvent, for example, nitromethane, acetic acid, sulfuric acid or the like, using a suitable nitrating agent, for example, concentrated nitric acid, fuming nitric acid, potassium nitrate, acetyl nitrate or the like to convert to general formula (51), and this is hydrolyzed for 1 to 10 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, water, ethanol, methanol, mixed solution thereof or the like, using a suitable base, for example, sodium hydroxide, potassium hydroxide or the like, or it is hydrolyzed for 1 to 10 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, water, ethanol, methanol or the like or mixed solution thereof, using a suitable acid, for example, hydrochloric acid, hydrobromic acid or the like, thereby converting to general formula (52). Next, the general formula (52) is reacted for 1 to 10 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, chloroform, methylene chloride, tetrahydrofuran, benzene, water or the like, using a suitable oxidizing agent, for example, manganese dioxide or the like to convert to general formula (53). This general formula (53) is reacted with malonic esters, for example, diethyl malonate or the like, for 2 to 24 hours at 25 to 100xc2x0 C. in a suitable solvent, for example, alcohol such as ethanol or methanol, tetrahydrofuran, N,N-dimethylformamide or the like in the presence of a suitable base, for example, sodium ethoxide, potassium ter-butoxide, potassium hydroxide or the like to convert to general formula (54), and then these are reacted with alkyl halide, for example, methyl iodide or the like, or aralkyl halide, for example, 4-methoxybenzyl chloride or the like, for 2 to 10 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, benzene, toluene, chloroform, methylene chloride, tetrahydrofuran or the like, using a suitable silver catalyst, for example, silver oxide, silver carbonate or the like, thus allowing to convert to the general formula (26).
Moreover, compounds represented by the general formula (54) can also be reacted for 2 to 6 hours at 0 to 120xc2x0 C. in a suitable solvent, for example, benzene, toluene, chloroform, methylene chloride, tetrahydrofuran or the like, using borate, for example, tetramethyloxonium borate or the like to convert to the general formula (26).
Moreover, compounds represented by a general formula (55), R being halogen, V being methylene and T1 being hydroxyl group among compounds represented by the general formula (10), can also be synthesized through processes shown in following Scheme 7. 
(wherein R1 and R2 are as described above, and hal. denotes a halogen atom)
Namely, compounds represented by general formula (56) are reacted with a suitable nitrite, for example, sodium nitrite, nitrous ester, for example, t-butyl nitrite or the like, and halide, for example, potassium chloride or potassium bromide or copper (I or II) halide, for example, copper chloride, copper bromide or copper iodide, for 1 to 8 hours at 20 to 50xc2x0 C. in a suitable solvent, for example, dimethyl sulfoxide, acetonitrile, acetic acid, water, mixed solvent thereof or the like to convert to compounds represented by general formula (57), and these are reduced at 0 to 100xc2x0 C. in a suitable solvent, for example, ethanol, methanol, isopropanol, water, mixed solution thereof or the like, using a suitable reducing agent, for example, sodium borohydride or the like, thus allowing to synthesize.
Moreover, compounds represented by the general formula (55) can also be obtained directly by reacting compounds represented by the general formula (56) with a suitable nitrite, for example, sodium nitrite, nitrous ester, for example, t-butyl nitrite or the like, and halide, for example, potassium chloride or potassium bromide or copper (I or II) halide, for example, copper chloride, copper bromide or copper iodide, for 0.5 to 2 hours at 0 to 50xc2x0 C. in a suitable solvent, for example, dimethyl sulfoxide, acetonitrile, acetic acid, water, mixed solvent thereof or the like.
Moreover, compounds represented by the general formula (56) can be obtained by hydrogenating compounds represented by general formula (58), R being nitro group, V being methylene and T1 being hydroxyl group among compounds represented by the general formula (10), for 2 to 24 hours at 25 to 80xc2x0 C. and at atmospheric pressure to 5 atm (507 KPa) in a suitable solvent, for example, ethanol, methanol, acetic acid, mixed solution thereof or the like in the presence of a suitable catalyst, for example, palladium on carbon, platinum oxide or the like (Scheme 8). 
(wherein A, Y, R1 and R2 are as described above)
Moreover, compounds represented by the general formula (56) can also be obtained by reacting compounds represented by general formula (58) with a suitable reducing agent, for example, reducing iron, tin, tin chloride (II), titanium trichloride or the like for 2 to 24 hours at 25 to 100xc2x0 C. in a suitable solvent, for example, ethanol, methanol, acetic acid, hydrochloric acid, water, mixed solution thereof or the like.
Describing the examples of the inventive compounds, the invention will be illustrated in more detail.